Linomide is a known anti-inflammatory drug. Recently we have synthesized a new analog of Linomide, linomide-5. The objective of this proposal is to develop linomide-5 as a therapeutic for treating diabetic retinopathy (DR) and age-related macular degeneration (AMD). Together, these diseases constitute the major causes of blindness worldwide. In both cases, retinal inflammation is a causative factor for the breakdown of the blood-retinal barrier, which leads to leakage of plasma and fluid into the retina, causing macular edema which is a leading cause of vision loss in diabetic patients and in patients with AMD. There is a dire need to develop effective therapies to treat both the inflammatory and retinal vascular leakage of the diseases. In Phase I studies, we have shown that linomide-5 is nearly ~70 fold more potent than Linomide in its anti-inflammatory activity. Further, we have demonstrated that this compound is effective in reducing vascular leakage and inflammation in multiple in vivo and in vitro models. Towards the development of a commercially viable therapeutic with sustained release, we have packaged linomide-5 into nanoparticles (L5-NPs). The goal of this proposal is to evaluate the efficacy of L5-NPs in preventing inflammation, vascular leakage, and loss of vision in animal models of DR and AMD. Furthermore, we will perform rigorous toxicity and pharmacokinetic studies in both rabbits and pigs to assess the safety of using L5-NPs in future human clinical trials. The completion of these studies will provide sufficient data that will enable us to file an investigative new drug application with the food and drug administration. We anticipate that L5-NPs will be useful in treating both DR and AMD, and could prove useful as a combinatorial therapy with other currently approved anti-angiogenic pharmaceuticals. PUBLIC HEALTH RELEVANCE: Retinal inflammation and vascular leakage or breakdown of the blood-retina barrier are early features of diabetic retinopathy (DR) and age-related macular degeneration (AMD) that leads to macular edema and causes a subsequent loss of vision. Currently, there are no effective drug treatments that address both vascular leakage and inflammation in these diseases. In this Phase II project, we will further investigate linomide-5, a new anti-inflammatory drug candidate, as a treatment for these diseases and determine its long- term efficacy, toxicity, and pharmacokinetics to obtain essential data for future human clinical trials. [unreadable] [unreadable] [unreadable]